Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization
Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization
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DOI：
10.3390/v12040426
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发表时间：
2020-04-01
期刊：
影响因子：
4.7
通讯作者：
Marcondes, Maria Cecilia Garibaldi
中科院分区：
文献类型：
--
作者：
Basova, Liana V.;Kesby, James P.;Marcondes, Maria Cecilia Garibaldi
甲基苯丙胺（Methe）滥用在免疫缺陷病毒（HIV）感染者中很常见。HIV-1调节蛋白，转录的反式激活因子（达特），已被描述为诱导脑基因转录的变化，这可能导致受损的奖励回路，以及炎症过程。在脑中具有多西环素诱导的达特蛋白表达的转基因小鼠中，即，在神经HIV的小鼠模型中，我们测试了由甲基苯丙胺致敏诱导的整体基因表达模式。甲基诱导的自发致敏包括每天重复注射甲基或生理盐水，持续7天，并在7天禁欲期后进行甲基激发。在甲基苯丙胺攻击后30分钟收集脑样品。我们研究了全球基因表达变化的尾壳核，行为和艾滋病病毒发病机制的相关领域，并进行了通路和转录因子的使用预测，使用系统生物学策略。我们发现，单独的达特表达在Meth攻击后对基因转录的影响非常有限。相反，在没有达特的情况下，甲基诱导的致敏诱导了基因转录的全面抑制。有趣的是，达特和甲基之间的相互作用广泛地防止了甲基诱导的整体转录抑制，通过维持调节途径，并导致基因表达谱更类似于对照。与线粒体健康、转录和翻译起始以及表观遗传控制相关的途径受到Meth及其与达特以反向方式相互作用的严重影响。一系列的系统策略已经预测了受这些相互作用影响的几个组分，包括线粒体途径、mTOR/RICTOR、AP-1转录因子以及参与转录和翻译的真核起始因子。尽管达特具有拮抗作用，但在相关基因网络中鉴定的一些基因仍然下调，如sirtuin 1和淀粉样前体蛋白（APP）。总之，脑中的达特表达具有较低的急性转录影响，但与甲氧苯甲烷敏化强烈相互作用，以改变整体转录组中的效应。
Methamphetamine (Meth) abuse is common among humans with immunodeficiency virus (HIV). The HIV-1 regulatory protein, trans-activator of transcription (Tat), has been described to induce changes in brain gene transcription that can result in impaired reward circuitry, as well as in inflammatory processes. In transgenic mice with doxycycline-induced Tat protein expression in the brain, i.e., a mouse model of neuroHIV, we tested global gene expression patterns induced by Meth sensitization. Meth-induced locomotor sensitization included repeated daily Meth or saline injections for seven days and Meth challenge after a seven-day abstinence period. Brain samples were collected 30 min after the Meth challenge. We investigated global gene expression changes in the caudate putamen, an area with relevance in behavior and HIV pathogenesis, and performed pathway and transcriptional factor usage predictions using systems biology strategies. We found that Tat expression alone had a very limited impact in gene transcription after the Meth challenge. In contrast, Meth-induced sensitization in the absence of Tat induced a global suppression of gene transcription. Interestingly, the interaction between Tat and Meth broadly prevented the Meth-induced global transcriptional suppression, by maintaining regulation pathways, and resulting in gene expression profiles that were more similar to the controls. Pathways associated with mitochondrial health, initiation of transcription and translation, as well as with epigenetic control, were heavily affected by Meth, and by its interaction with Tat in anti-directional ways. A series of systems strategies have predicted several components impacted by these interactions, including mitochondrial pathways, mTOR/RICTOR, AP-1 transcription factor, and eukaryotic initiation factors involved in transcription and translation. In spite of the antagonizing effects of Tat, a few genes identified in relevant gene networks remained downregulated, such as sirtuin 1, and the amyloid precursor protein (APP). In conclusion, Tat expression in the brain had a low acute transcriptional impact but strongly interacted with Meth sensitization, to modify effects in the global transcriptome.